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Nasopharyngeal carcinoma

Dr sreeleshRcc Trivandrum

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Introduction  

• Nasopharyngeal carcinoma is the predominant tumour type arising in the nasopharynx.(85%)

• Less common • Lymphoma ~10 %• Plasmacytoma • Rare types

– Sarcoma– Melanoma– Minor salivary gland tumours

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Unique nature Ca Nasopharynx

• Etiology

• Geographic distribution

• Pathology

• Staging

• Distant metastasis

• Treatment & Prognosis

• Recurrence

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Anatomy

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Lateral wall

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EPIDEMIOLOGY 

World wide

• ~80,000 new cases/year • 50,000 deaths/year.

• Regional differences– Endemic in southern China, Hong Kong– Rare in west– Intermediate in middle east.

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Incidence

• Increases after 20 years and decreases after 60 years

• M:F 3:1

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ETIOLOGY 

• Multifactorial

Endemic

Viral

Diet

Genetic

Non-endemic

Tobacco Alcohol

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Viral etiology

• Epstein-Barr virus

– Normal nasopharyngeal epithelia lack EBV

– EBV DNA and EBV gene were found in precursor lesions and tumour cells.

– Expression EBV latent proteins, including EBNA-1 and LMP-1 and LMP-2

– Patients also demonstrate specific serologic responses to various gene products of EBV (Ig A against EBV VCA)

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• Human papilloma virus

• HPV was detected in a small subset of carcinomas

• Considered extension of oropharyngal lesions

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Diet 

• The cooking of salt-cured food• volatile nitrosamines.

• Early childhood exposure to salted fish• High consumption of preserved or fermented foods

• Nitrosamines• bacterial mutagens• direct genotoxins• EBV-reactivating substances.

• The use of Chinese medicinal herbs• The consumption of rancid butter and sheep's fat

• butyric acid, a potential EBV activator

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Heredity 

• Increased incidence in families

• NPC has been associated with certain HLA haplotypes.

• Associated with genetic polymorphisms, such as CYP2A6• nitrosamine metabolizing gene.

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Molecular pathogenesis

• Copy number losses on chromosomes 1p, 3p, 9p, 9q, 11q, 13q, 14q and 16q and recurrent gains on chromosome 1q, 3q, 8q, 12p and 12q.

• TP53 and RB1,• p16 • RASSF1A• CCND1

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CLINICAL PRESENTATION

• Most common site of origin is fossa of Rosenmuller.• Patients may remain asymptomatic for a prolonged period.

• Most presents with locally advanced disease.

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Pattern of spread

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Painless neck mass 30-70 % /nodal metastasis

Hearing loss or ear drainage 25 % /ET tube involvement

Nasal bleeding or obstruction Nasal cavity

Cranial nerve deficitVI and V 2(V2 most commonly)facial pain

Cavernous sinus involvement

headaches Intracranial extension

Trismus pterygoid muscle invasion

Proptosis Orbit

neck discomfort. Retropharyngeal node involvement

9,10 ,11 CN Para pharyngeal space involvement

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Metastatic potential

• Most common site

• Cervical nodes• Up to 90 %• Bilateral in 50 % cases.• DM at diagnosis in 5 to 11 %

Distant metastasis

• The location and extent of cervical lymph node mets predict DM• Bone (75 percent), lung, liver, and distant nodes.

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Multiple paraneoplastic syndromes

• Neutrophilia • Fever of unknown origin• Hypertrophic osteoarthropathy• Dermatomyositis

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Histology

WHO classification of carcinoma of Nasopharynx

• Type I – Keratinizing squamous cell carcinoma • Type II – Non keratinizing carcinoma type

Differentiated carcinoma (type 2.1) Undifferentiated carcinoma (type 2.2)

• Type III – basaloid squamous cell carcinoma

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DIAGNOSTIC EVALUATION

• Clinical evaluation of the size and location of cervical lymph nodes

• Indirect nasopharyngoscopy to assess the primary tumor.

• Neurological examination of cranial nerves.

• Confirmation by biopsy of the primary or metastatic node.

• CT/MRI of base of skull to root of neck

• Chest X ray

• Blood counts,RFT,LFT

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• Bone scan – Clinical symptoms– Biochemical evidence– N2/N3 nodal disease

• EBV viral capsid antigen and EBV DNA

• PET-CT if available (N3 nodes )

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CT or MRI

• MRI preferred over CT

• Better Identification

– Tumor invasion into soft tissue– Pharyngobasilar fascia obliteration– Invasion into the sinus of Morgagni– Skull base invasion – Lymph node metastases in the carotid and retropharyngeal spaces

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EPSTEIN-BARR VIRUS TESTING

• Pre-treatment levels for its prognostic contribution.

• Non-invasive screening– The combination of IgA VCA and plasma EBV DNA– Southern china – Elevated titer may precede NPC many years

• To predict risk of relapse

• Monitoring for disease recurrence

• Alternative to histopathologic diagnosis of nasopharyngeal carcinoma• EBV-specific antibody-based assays• Plasma EBV DNA levels• BARF1 oncogene mRNA detection from nasopharyngeal brushings

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STAGING 

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Prognostic factors

• T stage• N stage

• Pretreatment EBV levels• Post treatment EBV levels• Young females –better• EGF receptor expression-poor prognosis

• Treatment related factros• Refinement In RT• Chemotherapy

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Treatment

• Better RT technique• Better chemotherapy• Monitoring • Improvement in Imaging

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• Radiotherapy

• Chemotherapy

• Surgery

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• Role of surgery

• Not indicated as a primary treatment• To obtain biopsy• Neck dissection

– Residual neck nodes following RT– Isolated neck recurrence

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Radiotherapy

• Megavoltage RT is the standard treatment

Rx of choice due to:

1. Early bilateral LN mets2. Involvement of retropharyngeal node of Rouvier which cannot be

surgically removed3. Deep seated location and proximity to vital structures4. Highly radiosensitive nature

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Dose of RT

• Primary should receive 70Gy/35# over 7 weeks.

• Involved nodes should receive 66-70Gy/33-35# over 6 to 7 weeks

• Uninvolved nodes receive 50Gy/25# over 5 weeks

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Dose alternation ??

• Dose less than 60 Gy : Less local control

• No role of dose escalation with brachy or SRS boost >70 Gy

• Dose > 80 Gy : Temporal lobe necrosis: Torrential epistaxis

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Time and Fractionation

• Prolongation of treatment significantly jeopardizes local control

• Hyper fractionation : no improvement in LC significant toxicities.

• Dose >2 Gy is associated with TLN

1.8-2 Gy # is the recommended dose

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Radiation Technique

Until 1990

• 2D –CRT

• High toxicities• Higher chance of LR• Permanent parotid damage

• Worse for locally advanced disease

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IMRT

• Advanced form of 3-D RT

• Improve dose conformity• Better protection of the adjacent organs• Better local control for locally advanced disease.

• Lower incidence of xerostomia• pre-serves middle ear function• Better quality of life

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Disadvantages

• Cost• Marginal miss• Expertise

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• 2003 -2008• 616 patients• non-metastatic • stage I to IVb NPC • 2D-CRT vs. IMRT

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Results

IMRT 2D-RT

5 year local control rate 90.5 84.7

T3 91% 80%

T4 81.5% 62.2%

nodal relapse-free survival

92.4% 92.9%

5-year overall survival 79.6% 67.1%

Toxicities Less More

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Role of Chemotherapy

• Induction • Concurrent• Adjuvant

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Induction

Theoretical advantages

• Will be better tolerated• Eradicating micro metastases early.• Shrinking of the primary tumour to give a wider margin for irradiation

• Better DFS no OS benefit

• NCCN considers induction chemotherapy as cat 3 recommendation

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NACT

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Concurrent

• Most studied• More EFS and OS• Sensitize tumour to the effects of RT • Better LC rates compared to RT alone• Improvement in distant failure-free rate

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U.S. Intergroup 0099

CRT RT

3 year PFS 69% 24%

3 year OS 78% 47%

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U.S. Intergroup 0099

• Issues– Flawed study design

• Are the benefits from chemo due to concurrent administration, adjuvant, or both?

– Terminated early after interim analysis showed survival benefit– RT alone arm performed worse than expected– Old RT techniques– Many patients enrolled had WHO type I NPC (not EBV-associated)– Adjuvant PF chemotherapy only feasible in some patients

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Adjuvant chemotherapy

• Intergroup Study 0099 trial

• Cisplatin +5 FU for 3 cycles • Indicated in

• Patients in good PS

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Chinese phase III trial

• 508 patients• Nonmetastatic advanced NPC

• Adjuvant chemo no advantage

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Meta-analysis in NPC

• 8 trials, 1753 pts

6% absolute survival benefit at 5 years

Greatest benefit from concurrent chemo

HR=0.60 (concurrent)HR=0.97 (adjuvant)HR=0.99 (induction)

Baujat, IJROBP, 2006

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Chemoradiation-metaanalysis

• Induction chemo Radiotherapy ? DFS

• Radiotherapy Adjuvant chemo (NS) • Concurrent ChemoRT (OS,DFS,DM)

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Metastatic disease at presentation

• 5- 10 % cases

• Bone Mets –poor prognosis

Favorable group

• Chemo with (CDDP+5FU ) X 2-3 cycles reassess CR CRT

• Otherwise palliation

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Treatment

• T1 N0 M0» RT alone

• T2,T3,T4 or N+,M0» ChemoRT» Cisplatin based 3 weekly

• Metastatic » Platinum based combination CR radical RT

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POSTTREATMENT FOLLOW-UP

Documentation of remission 

• Clinical • Endoscopic • Imaging

3 months • MRI scan of the skull base and neck• CT head &neck• PET-CT

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Follow up

• 3 monthly follow up for 2 years• 4-6 monthly for 3-5 years• Annually after 5 years

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Management of relapse

• Local relapse– Brach therapy with Au 198 (small lesions)– Salvage surgery

• No intracranial extension• No bone erosion

• Nodal relapse – Salvage neck dissection

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Thank you